V_H replacement in rearranged immunoglobulin genes

Examples suggesting that all or part of the V<sub>H</sub> segment of a rearranged V<sub>H</sub>DJ<sub>H</sub> may be replaced by all or part of another V<sub>H</sub> have been appearing since the 1980s. Evidence has been presented of two rather different types of replacement. One of these has gained acceptance and has now been clearly demonstrated to occur. The other, proposed more recently, has not yet gained general acceptance because the same effect can be produced by polymerase chain reaction artefact. We review both types of replacement including a critical examination of evidence for the latter. The first type involves RAG proteins and recombination signal sequences (RSS) and occurs in immature B cells. The second was also thought to be brought about by RAG proteins and RSS. However, it has been reported in hypermutating cells which are not thought to express RAG proteins but in which activation-induced cytidine deaminase (AID) has recently been shown to initiate homologous recombination. Re-examination of the published sequences reveals AID target sites in V<sub>H</sub>-V<sub>H</sub> junction regions and examples that resemble gene conversion

Making Associativity Operational

The purpose of this paper is to propose an operational idea for developing algebraic thinking in the absence of alphanumeric symbols. The paper reports on a design experiment encouraging preschool children to use the associative property algebraically. We describe the theoretical basis of the design, the tasks used, and examples of algebraic thinking in 5–6-year-old children. Theoretically, the paper makes a critical distinction between operational and structural meanings of the notion of equality. We argue that mathematical thinking involving equality among young learners can comprise both an operational and a structural conception and that the operational conception has a side that is productively linked to the structural conception. Using carefully designed hands-on tasks, the crux of the paper is the realization of algebraic thinking (in verbal mathematics) as operationally experienced in the ability to transform one number structure, with a quantity that is subject to change, into another through equality-preserving transformations

Total syntheses of shizukaols A and E

Shizukaols possess a common heptacyclic framework containing more than ten contiguousstereocenters and potential biological activities. Here we report that the total syntheses ofshizukaols A (1)and E(2), two lindenane-type dimers from the Chloranthaceae family, areachieved via a modified biomimetic Diels–Alder reaction. The common crucial biomimetic diene23and ethylene species (6,17) are obtained through either a highlyZ-selective olefination ofα-siloxy ketone with ynolate anions or an intramolecular Horner–Wadsworth–Emmons olefinationfrom commercially available Wieland–Miescher ketone (7). This synthetic approach here opensup practical avenues for the total syntheses of the intriguing Chloranthaceae family members, aswell as the understanding of their relevant biological action in natur

Quantitative metric profiles capture three-dimensional temporospatial architecture to discriminate cellular functional states

<p>Abstract</p> <p>Background</p> <p>Computational analysis of tissue structure reveals sub-visual differences in tissue functional states by extracting quantitative signature features that establish a diagnostic profile. Incomplete and/or inaccurate profiles contribute to misdiagnosis.</p> <p>Methods</p> <p>In order to create more complete tissue structure profiles, we adapted our cell-graph method for extracting quantitative features from histopathology images to now capture temporospatial traits of three-dimensional collagen hydrogel cell cultures. Cell-graphs were proposed to characterize the spatial organization between the cells in tissues by exploiting graph theory wherein the nuclei of the cells constitute the <it>nodes </it>and the approximate adjacency of cells are represented with <it>edges</it>. We chose 11 different cell types representing non-tumorigenic, pre-cancerous, and malignant states from multiple tissue origins.</p> <p>Results</p> <p>We built cell-graphs from the cellular hydrogel images and computed a large set of features describing the structural characteristics captured by the graphs over time. Using three-mode tensor analysis, we identified the five most significant features (metrics) that capture the compactness, clustering, and spatial uniformity of the 3D architectural changes for each cell type throughout the time course. Importantly, four of these metrics are also the discriminative features for our histopathology data from our previous studies.</p> <p>Conclusions</p> <p>Together, these descriptive metrics provide rigorous quantitative representations of image information that other image analysis methods do not. Examining the changes in these five metrics allowed us to easily discriminate between all 11 cell types, whereas differences from visual examination of the images are not as apparent. These results demonstrate that application of the cell-graph technique to 3D image data yields discriminative metrics that have the potential to improve the accuracy of image-based tissue profiles, and thus improve the detection and diagnosis of disease.</p

Splenectomy Normalizes Hematocrit in Murine Polycythemia Vera

Splenic enlargement (splenomegaly) develops in numerous disease states, although a specific pathogenic role for the spleen has rarely been described. In polycythemia vera (PV), an activating mutation in Janus kinase 2 (JAK2V617) induces splenomegaly and an increase in hematocrit. Splenectomy is sparingly performed in patients with PV, however, due to surgical complications. Thus, the role of the spleen in the pathogenesis of human PV remains unknown. We specifically tested the role of the spleen in the pathogenesis of PV by performing either sham (SH) or splenectomy (SPL) surgeries in a murine model of JAK2V617F-driven PV. Compared to SH-operated mice, which rapidly develop high hematocrits after JAK2V617F transplantation, SPL mice completely fail to develop this phenotype. Disease burden (JAK2V617) is equivalent in the bone marrow of SH and SPL mice, however, and both groups develop fibrosis and osteosclerosis. If SPL is performed after PV is established, hematocrit rapidly declines to normal even though myelofibrosis and osteosclerosis again develop independently in the bone marrow. In contrast, SPL only blunts hematocrit elevation in secondary, erythropoietin-induced polycythemia. We conclude that the spleen is required for an elevated hematocrit in murine, JAK2V617F-driven PV, and propose that this phenotype of PV may require a specific interaction between mutant cells and the spleen

Oral Ondansetron Administration in Emergency Departments to Children with Gastroenteritis: An Economic Analysis

Stephen Freedman and colleagues performed a cost analysis of the routine administration of ondansetron in both the United States and Canada and show that its routine administration to eligible children in such settings could provide substantial benefit

Genome-assisted prediction of a quantitative trait measured in parents and progeny: application to food conversion rate in chickens

Accuracy of prediction of yet-to-be observed phenotypes for food conversion rate (FCR) in broilers was studied in a genome-assisted selection context. Data consisted of FCR measured on the progeny of 394 sires with SNP information. A Bayesian regression model (Bayes A) and a semi-parametric approach (Reproducing kernel Hilbert Spaces regression, RKHS) using all available SNPs (p = 3481) were compared with a standard linear model in which future performance was predicted using pedigree indexes in the absence of genomic data. The RKHS regression was also tested on several sets of pre-selected SNPs (p = 400) using alternative measures of the information gain provided by the SNPs. All analyses were performed using 333 genotyped sires as training set, and predictions were made on 61 birds as testing set, which were sons of sires in the training set. Accuracy of prediction was measured as the Spearman correlation (r¯S) between observed and predicted phenotype, with its confidence interval assessed through a bootstrap approach. A large improvement of genome-assisted prediction (up to an almost 4-fold increase in accuracy) was found relative to pedigree index. Bayes A and RKHS regression were equally accurate (r¯S = 0.27) when all 3481 SNPs were included in the model. However, RKHS with 400 pre-selected informative SNPs was more accurate than Bayes A with all SNPs

A statistical approach to quantitative data validation focused on the assessment of students' perceptions about biotechnology

Student awareness levels are frequently used to evaluate the effectiveness of educational policies to promote scientific literacy. Over the last years several studies have been developed to assess students' perceptions towards science and technology, which usually rely on quantitative methods to achieve broad characterizations, and obtain quantifiable and comparable data. Although the usefulness of this information depends on its validity and reliability, validation is frequently neglected by researchers with limited background in statistics. In this context, we propose a guideline to implement a statistical approach to questionnaire validation, combining exploratory factor analysis and reliability analysis. The work focuses on the psychometric analysis of data provided by a questionnaire assessing 1196 elementary and high school students' perceptions about biotechnology. Procedural guidelines to enhance the efficiency of quantitative inquiry surveys are given, by discussing essential methodological aspects and relevant criteria to integrate theory into practice.The authors are grateful to all the participant teachers and students that contributed to gather the data presented and to Catarina L. Santos for useful comments and suggestions on the manuscript. Maria Joao Fonseca was supported by the FCT fellowship SFRH/BD/37389/2007 and this work was sponsored by a research grant (PTDC/AGR-PRO/111857/2009) from Fundacao para a Ciencia e Tecnologia (FCT, Portugal)

Differential Disclosure Across Social Network Ties Among Women Living with HIV

Women’s disclosure of their HIV serostatus across social network ties was examined in a sample of women living in Los Angeles (n = 234), using multivariate random intercept logistic regressions. Women with disclosure-averse attitudes were less likely to disclose, while women with higher CD4+ counts were significantly more likely to disclose, regardless of relationship type. Relative to all other types of relationships, spouses/romantic partners were greater than four times more likely to be the targets of disclosure. Women were more than 2.5 times more likely to disclose to a given network member if that target provided the woman with social support. Social network members whom women believed to be HIV-positive were more than 10 times more likely to be the targets of disclosure. The implications for how social roles and social identities are manifest in these results are discussed, including the implications such an interpretation has for future prevention research